New therapeutic approaches are needed for patients with thyroid cancers refractory to radioiodine treatment. Inhibitors interfering with the interaction of bromodomain and extra terminal domain (BET) proteins with acetylated histones have potent anti-tumor effects in hematological malignancy and a few solid tumors. However, it is not known whether a BET inhibitor such as JQ1 is effective against thyroid cancer. Using a preclinical mouse model mimicking anaplastic thyroid cancer (ThrbPV/PVKrasG12D mice), we evaluated the effect of JQ1 on thyroid carcinogenesis. We found JQ1 treatment significantly prolonged survival, inhibited tumor growth, and attenuated transcriptional programs critical for tumor cell proliferation. Our preclinical findings indicated that use of BET inhibitors could be a promising therapeutic strategy for anaplastic thyroid cancer. Indeed, we further tested the efficacy of JQ1 in 4 human ATC cells. JQ1 markedly inhibited proliferation of 4 ATC cell lines by suppression of MYC and elevation of p21and p27 to decrease phosphorylated Rb to delay cell cycle progression from the G0/G1 phase to the S phase. JQ1 blocked cell invasion by attenuating epithelial mesenchymal transition signals. These cell-based studies were further confirmed in xenograft studies in that the size and rate of tumor growth was inhibited by JQ1 via inhibition of p21-Cyclin/CDK-Rb-E2F signaling. These novel results suggest targeting MYC protein could be a potential novel treatment modality for human ATC for which effective treatment options are limited.